Cloning and mutation analysis of ZFP276 as a candidate tumor suppressor in breast cancer

Wong, Jasmine; Gökgöz, Nalan; Alon, Noa; Andrulis, Irene L.; Buchwald, Manuel

doi:10.1007/s10038-003-0088-1

Cited by 12 publications

(9 citation statements)

References 11 publications

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“…For example, the ZNF276 intronic variant rs12925026 is associated at genome-wide significance with nonmelanoma skin cancer (29). ZNF276 overlaps FANCA in a tail-to-tail manner (30). The genetically regulated predictor model for ZNF276 expression was fit using gene expression measured in GTEx breast tissues but neither this data set nor any of the other data sets could capture a predictor model for FANCA expression.…”

Section: Discussionmentioning

confidence: 99%

“…Several members of the FA family of proteins have been implicated in breast and ovarian cancer predisposition including, BRCA2 (FANCD1), BRIP1 (FANCJ), PALB2 (FANCN), and FANCM and it is possible that FANCA may represent another or possibly the true target breast cancer susceptibility gene in this region given this biological function and its overlap with ZNF276 (31,32). ZNF276 in its own right has also been implicated as a candidate tumor suppressor gene in breast cancer (30).…”

Section: Discussionmentioning

confidence: 99%

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Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Kar¹,

Considine²,

Tyrer³

et al. 2020

Preprint

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Familial, genome-wide association (GWAS), and sequencing studies and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWAS) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through novel application of a pleiotropy-guided conditional/conjunction false discovery rate approach for the first time in the setting of a TWAS. This identified 14 new candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 new candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were > 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. Overlaying candidate causal risk variants identified by GWAS fine mapping onto expression prediction models for genes at known loci suggested that the association for 55% of these genes was driven by the underlying GWAS signal. SignificanceThe 22 new genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Kar¹,

Considine²,

Tyrer³

et al. 2020

Preprint

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show abstract

“…It is attractive to hypothesize that the rate-limiting step in vertebrate steroid hormone biosynthesis is also specifically regulated by unidentified transcriptional and/or splicing regulator(s). Whereas no apparent orthologs of ouib are found in vertebrates, their genomes possess a ZAD-ZFP gene called ZFP276 , which is a tumor suppressor gene [ 66 ]. Interestingly a ecd ortholog is also found in humans and may also contribute to the malignancy of certain tumor types [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

The Drosophila Zinc Finger Transcription Factor Ouija Board Controls Ecdysteroid Biosynthesis through Specific Regulation of spookier

et al. 2015

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Steroid hormones are crucial for many biological events in multicellular organisms. In insects, the principal steroid hormones are ecdysteroids, which play essential roles in regulating molting and metamorphosis. During larval and pupal development, ecdysteroids are synthesized in the prothoracic gland (PG) from dietary cholesterol via a series of hydroxylation and oxidation steps. The expression of all but one of the known ecdysteroid biosynthetic enzymes is restricted to the PG, but the transcriptional regulatory networks responsible for generating such exquisite tissue-specific regulation is only beginning to be elucidated. Here, we report identification and characterization of the C2H2-type zinc finger transcription factor Ouija board (Ouib) necessary for ecdysteroid production in the PG in the fruit fly Drosophila melanogaster. Expression of ouib is predominantly limited to the PG, and genetic null mutants of ouib result in larval developmental arrest that can be rescued by administrating an active ecdysteroid. Interestingly, ouib mutant animals exhibit a strong reduction in the expression of one ecdysteroid biosynthetic enzyme, spookier. Using a cell culture-based luciferase reporter assay, Ouib protein stimulates transcription of spok by binding to a specific ~15 bp response element in the spok PG enhancer element. Most remarkable, the developmental arrest phenotype of ouib mutants is rescued by over-expression of a functionally-equivalent paralog of spookier. These observations imply that the main biological function of Ouib is to specifically regulate spookier transcription during Drosophila development.

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“… 30 ZNF276 overlaps FANCA (MIM: 607139) in a tail-to-tail manner. 31 The genetically regulated predictor model for ZNF276 expression was fit using gene expression measured in GTEx breast tissues, but neither this dataset nor any of the other datasets could capture a predictor model for FANCA expression. FANCA encodes one of eight subunits that together form the core Fanconi Anemia (FA) complex that repairs blockages in DNA replication due to cross-linking.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Kar

Considine

Tyrer

et al. 2021

Human Genetics and Genomics Advances

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Summary Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

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Cloning and mutation analysis of ZFP276 as a candidate tumor suppressor in breast cancer

Cited by 12 publications

References 11 publications

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

The Drosophila Zinc Finger Transcription Factor Ouija Board Controls Ecdysteroid Biosynthesis through Specific Regulation of spookier

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

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